A Water-Mediated and Substrate-Assisted Catalytic Mechanism for<i>Sulfolobus solfataricus</i>DNA Polymerase IV

Wang, Lihua; Yu, Xinyun; Hu, Po; Broyde, Suse; Zhang, Yingkai

doi:10.1021/ja068821c

Cited by 122 publications

(199 citation statements)

References 69 publications

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“…Acetylcholinesterase has been simulated by QM/ MM-FE with an emphasis on the effects of conformational dynamics on the reaction process [130,131]. cAMP-dependent protein kinase [132,133], histone lysine methyltransferase SET7/9 [134,135,136], and bacterial peptide deformylase [137,138] have been studied by the QM/MM-FE method. The reaction mechanism of methane monooxygenase has been explored in detail by Friesner and co-workers [139,140], as well as the P450cam pathway [141].…”

Section: Applications Of Ab Initio Qm/mm Methodsmentioning

confidence: 99%

Free Energies of Chemical Reactions in Solution and in Enzymes with Ab Initio Quantum Mechanics/Molecular Mechanics Methods

Yang

2008

Annu. Rev. Phys. Chem.

417

401

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Combined QM/MM methods provide an accurate and efficient energetic description of complex chemical and biological systems, leading to significant advances in the understanding of chemical reactions in solution and in enzymes. Progress in QM/MM methodology and application will be reviewed, with a focus on ab initio QM based approaches. Ab initio QM/MM methods capitalize on the accuracy and reliability of the associated quantum mechanical approaches, however at a much higher computational cost compared with semiempirical quantum mechanical approaches. Thus reaction path and activation free energy calculations based on ab initio QM/MM methods encounter unique challenges in simulation timescales and phase space sampling. Recent developments overcoming these challenges and enabling accurate free energy determination for reaction processes in solution and enzymes will be featured in this review, along with applications.

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Section: Applications Of Ab Initio Qm/mm Methodsmentioning

confidence: 99%

Free Energies of Chemical Reactions in Solution and in Enzymes with Ab Initio Quantum Mechanics/Molecular Mechanics Methods

Yang

2008

Annu. Rev. Phys. Chem.

417

401

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“…Such water-assisted proton transfer mechanisms have also been found in other enzyme systems. 32,33 We therefore propose a new model that Glu217 acts as the general base to activate the zinccoordinated water through the bridging water (Fig. 2).…”

Section: Mechanism Bmentioning

confidence: 99%

A theoretical study on the catalytic mechanism of Mus musculus adenosine deaminase

Zou

Quan

et al. 2010

J Comput Chem

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The catalytic mechanism of Mus musculus adenosine deaminase (ADA) has been studied by quantum mechanics and two-layered ONIOM calculations. Our calculations show that the previously proposed mechanism, involving His238 as the general base to activate the Zn-bound water, has a high activation barrier of about 28 kcal/mol at the proposed rate-determining nucleophilic addition step, and the corresponding calculated kinetic isotope effects are significantly different from the recent experimental observations. We propose a revised mechanism based on calculations, in which Glu217 serves as the general base to abstract the proton of the Zn-bound water, and the protonated Glu217 then activates the substrate for the subsequent nucleophilic addition. The rate-determining step is the proton transfer from Zn-OH to 6-NH(2) of the tetrahedral intermediate, in which His238 serves as a proton shuttle for the proton transfer. The calculated kinetic isotope effects agree well with the experimental data, and calculated activation energy is also consistent with the experimental reaction rate.

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“…Then, two conserved tyrosine residues enter the insertion site and sterically exclude the nascent base pair. Evolving charge dynamics during the nucleotidyltransfer reaction is an important element in the replication process and has been computationally elucidated for Dpo4 [34].…”

Section: Dpo4: Stepwise Translocationmentioning

confidence: 99%

Lesion processing: high-fidelity versus lesion-bypass DNA polymerases

Broyde¹,

Wang²,

Rechkoblit³

et al. 2008

Trends in Biochemical Sciences

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When a high-fidelity DNA polymerase encounters certain DNA-damage sites, its progress can be stalled and one or more lesion-bypass polymerases are recruited to transit the lesion. Here, we consider two representative types of lesions: (i) 7,8-dihydro-8-oxogua-nine (8-oxoG), a small, highly prevalent lesion caused by oxidative damage; and (ii) bulky lesions derived from the environmental pre-carcinogen benzo [a]pyrene, in the high-fidelity DNA polymerase Bacillus fragment (BF) from Bacillus stearothermophilus and in the lesion-bypass DNA polymerase IV (Dpo4) from Sulfolobus solfataricus. The tight fit of the BF polymerase around the nascent base pair contrasts with the more spacious, solvent-exposed active site of Dpo4, and these differences in architecture result in distinctions in their respective functions: one-step versus stepwise polymerase translocation, mutagenic versus accurate bypass of 8-oxoG, and polymerase stalling versus mutagenic bypass at bulky benzo[a]pyrene-derived lesions. Lesions and DNA polymerasesUntil 1999, it was widely understood that bacteria have three DNA polymerases and mammals have five [1]. In 1999, however, an entirely new category of polymerases was discovered in prokaryotes and eukaryotes [2-4] -the lesion-bypass DNA polymerases. The function of lesion-bypass polymerases is to replicate past lesion-containing DNA templates in a process called translesion synthesis [5][6][7]. Now at least 16 DNA polymerases are known in eukaryotes [8] and five in bacteria [9]. Furthermore, since 1999, crystal structures of DNA polymerases, including those containing lesions, have provided new structural insights into the mechanistic aspects of translesion synthesis and polymerase stalling associated with DNA lesions. For a review of the structures and mechanisms of DNA polymerases up to the year 2005, see Ref.[10].Here, we discuss the structural and functional features of representative high-fidelity and lesion-bypass DNA polymerases (Box 1) and how these features affect the processing of certain forms of DNA damage. The lesions considered are derived from reactions of intermediates produced by endogenous sources or from the metabolic activation of environmental genotoxic

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A Water-Mediated and Substrate-Assisted Catalytic Mechanism forSulfolobus solfataricusDNA Polymerase IV

Cited by 122 publications

References 69 publications

Free Energies of Chemical Reactions in Solution and in Enzymes with Ab Initio Quantum Mechanics/Molecular Mechanics Methods

Free Energies of Chemical Reactions in Solution and in Enzymes with Ab Initio Quantum Mechanics/Molecular Mechanics Methods

A theoretical study on the catalytic mechanism of Mus musculus adenosine deaminase

Lesion processing: high-fidelity versus lesion-bypass DNA polymerases

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